8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives

ABSTRACT

The present invention relates to novel 8-azabicyclo[3.2.1.]oct-2-ene and -octane derivatives which are found to be cholinergic ligands at the nicotinic Acetyl Choline Receptors. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of chemical substances.

TECHNICAL FIELD

[0001] The present invention relates to novel8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives which are found tobe cholinergic ligands at the nicotinic Acetyl Choline Receptors.

[0002] Due to their pharmacological profile the compounds of theinvention may be useful for the treatment of diseases or disorders asdiverse as those related to the cholinergic system of the centralnervous system (CNS), diseases or disorders related to smooth musclecontraction, endocrine diseases or disorders, diseases or disordersrelated to neurodegeneration, diseases or disorders related toinflammation, pain, and withdrawal symptoms caused by the termination ofabuse of chemical substances.

BACKGROUND ART

[0003] The endogenous cholinergic neurotransmitter, acetylcholine, exertits biological effect via two types of cholinergic receptors, themuscarinic Acetyl Choline Receptors (mAChR) and the nicotinic AcetylCholine Receptors (nAChR).

[0004] As it is well established that muscarinic ACh receptors dominatequantitatively over nicotinic ACh receptors in the brain area importantto memory and cognition, and much research aimed at the development ofagents for the treatment of memory related disorders have focused on thesynthesis of muscarinic ACh receptor modulators.

[0005] Recently, however, an interest in the development of nicotinicACh receptor modulators has emerged. Several diseases are associatedwith degeneration of the cholinergic system i.e. senile dementia of theAlzheimer type, vascular dementia and cognitive impairment due to theorganic brain damage disease related directly to alcoholism. Indeedseveral CNS disorders can be attributed to a cholinergic deficiency, adopaminergic deficiency, an adrenergic deficiency or a serotonergicdeficiency.

[0006] The present invention is devoted to the provision novel nicotinicreceptor modulators useful for therapy or diagnosis, which modulatorsare structurally close analogues of the compounds described in WO98/54181 (NeuroSearch A/S).

SUMMARY OF THE INVENTION

[0007] The present invention is devoted to the provision novel nicotinicreceptor modulators, which modulators are useful for the treatment ofdiseases or disorders related to the cholinergic receptors, and inparticular the nicotinic ACh receptor (nAChR).

[0008] Due to their pharmacological profile the compounds of theinvention may be useful for the treatment of diseases or disorders asdiverse as those related to the cholinergic system of the centralnervous system (CNS), diseases or disorders related to smooth musclecontraction, endocrine diseases or disorders, diseases or disordersrelated to neurodegeneration, diseases or disorders related toinflammation, pain, and withdrawal symptoms caused by the termination ofabuse of chemical substances.

[0009] The compounds of the invention may also be useful as diagnostictools or monitoring agents in various diagnostic methods, and inparticular for in vivo receptor imaging (neuroimaging), and they may beused in labelled or unlabelled form.

[0010] In its first aspect the invention provides chemical compoundshaving the general formula

[0011] in labelled or unlabelled form, or any of its enantiomers or anymixture thereof, or a pharmaceutically acceptable salt thereof;

[0012] wherein

[0013]- - - represents a single or a double bond;

[0014] R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, a mono- or polycyclic aryl group, or aralkyl; and

[0015] R¹ represents a group of the formula

[0016] wherein

[0017] R² represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, amino or a fluorescent group; or

[0018] R¹ represents an mono- or polycyclic aryl group, which aryl groupis substituted one or more times with substituents selected from thegroup consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl,alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,aryloxy, alkylcarbonyloxy, halogen, OCF₃, CN, amino, carbamoyl, nitro, amono- or polycyclic aryl group, a monocyclic 5- or 6- membered,saturated, partially saturated or unsaturated heterocyclic group, and agroup of the formula —X—R′(—Y—R″)_(n); wherein X and Y independently ofeach another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group; or

[0019] R¹ represents a monocyclic 5- or 6- membered, saturated,partially saturated or unsaturated heterocyclic group, whichheterocyclic group may be substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy,alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen, CF₃,OCF₃, CN, sulfanyl, nitro, a mono- or polycyclic aryl group, amonocyclic 5- or 6- membered, saturated, partially saturated orunsaturated heterocyclic group, and a group of the formula—X—R′(—Y—R″)_(n); wherein X and Y independently of each anotherrepresent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independentlyof each another represent alkyl or cycloalkyl; or a fluorescent group;or

[0020] R¹ represents a bi-cyclic heterocyclic group composed of amonocyclic 5- or 6-membered heterocyclic group with one heteroatom,fused to a benzene ring or fused to another monocyclic 5- or 6-membered, saturated, partially saturated or unsaturated heterocyclicgroup, all of which is substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy,alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen, CF₃,OCF₃, CN, sulfanyl, amino, nitro, a mono- or polycyclic aryl group, amonocyclic 5- or 6- membered, saturated, partially saturated orunsaturated heterocyclic group, and a group of the formula—X—R′(—Y—R″)_(n); wherein X and Y independently of each anotherrepresent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independentlyof each another represent alkyl or cycloalkyl; or a fluorescent group.

[0021] In a second aspect the invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention or a pharmaceutically acceptableaddition salt thereof, together with at least one pharmaceuticallyacceptable carrier or diluent.

[0022] In a third aspect the invention provides an assay kit comprisingthe composition according to the invention in a unit dosage form in asuitable container.

[0023] In a fourth aspect the invention relates to a use of the chemicalcompound of the invention for the manufacture of a medicament for thetreatment or alleviation of a disease or disorder of a living animalbody, including a human, which disease or disorder is responsive to theaction of a nicotinic Acetyl Choline Receptor (nAChR) modulator.

[0024] A fifth aspect of the invention relates to the use of thechemical compound of the invention or any of its enantiomers or anymixture thereof, in labelled or unlabelled form, for the manufacture ofa diagnostic agent for the diagnosis of a disorder or disease of aliving animal body, including a human, which disease or disorder isresponsive to the action of a nicotinic Acetyl Choline Receptor (nAChR)modulator, or a serotonin receptor modulator.

[0025] A sixth aspect of the invention provides a method for thepreparation of the compounds according to the invention, which methodcomprises

[0026] A) the step of reacting a compound having the formula

[0027] wherein R is as defined herein, with a compound of the formulaR¹—Li,

[0028] wherein R¹ is as defined herein, followed by dehydration of thecompound obtained; or

[0029] B) the step of reacting a compound having the formula

[0030] wherein R is as defined herein, with a compound of formula R¹—X,

[0031] wherein R¹ is as defined herein,

[0032] and X represents halogen, boronic acid, or trialkylstannyl; or

[0033] C) the step of reducing a compound having the formula

[0034] wherein R¹ is as defined herein.

[0035] A seventh aspect of the invention provides a method of thetreatment or alleviation of a disease or disorder of a living animalbody, including a human, which disease or disorder is responsive to theaction of a nicotinic Acetyl Choline Receptor (nAChR) modulator, whichmethod comprises the step of administering to such a living animal body,including a human, in need thereof a therapeutically effective amount ofthe chemical compound of the invention

[0036] A last aspect of the invention provides a method for thenon-invasive determination of the distribution of a tracer compoundinside a whole, intact living animal or human body using a physicaldetection method, wherein the tracer compound is a compound according tothe invention or any of its enantiomers or any mixture thereof, or apharmaceutically acceptable salt thereof, in labelled or unlabelledform.

[0037] Other objects of the invention will be apparent to the personskilled in the art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION Novel 8-azabicyclo[3.2.1]oct-2-eneand -octane Derivatives

[0038] In its first aspect the invention provides novel8-azabicyclo[3.2.1]oct-2-ene or -octane derivatives. The8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives of the inventionmay be characterised by being a chemical compound of the general formula1:

[0039] in labelled or unlabelled form, or any of its enantiomers or anymixture thereof, or a pharmaceutically acceptable salt thereof;

[0040] wherein

[0041]- - - represents a single or a double bond;

[0042] R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, a mono- or polycyclic aryl group, or aralkyl; and

[0043] R¹ represents a group of the formula

[0044] wherein R² represents hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl-alkyl, amino, or a fluorescent group; or

[0045] R¹ represents an mono- or polycyclic aryl group, which aryl groupis substituted one or more times with substituents selected from thegroup consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl,alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,aryloxy, alkylcarbonyloxy, halogen, OCF₃, CN, amino, carbamoyl, nitro, amono- or polycyclic aryl group, a monocyclic 5- or 6- membered,saturated, partially saturated or unsaturated heterocyclic group, and agroup of the formula —X—R′(—Y—R″)_(n); wherein X and Y independently ofeach another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group; or

[0046] R¹ represents a monocyclic 5- or 6- membered, saturated,partially saturated or unsaturated heterocyclic group, whichheterocyclic group may be substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy,alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen, CF₃,OCF₃, CN, sulfanyl, nitro, a mono- or polycyclic aryl group, amonocyclic 5- or 6- membered, saturated, partially saturated orunsaturated heterocyclic group, and a group of the formula—X—R′(—Y—R″)_(n); wherein X and Y independently of each anotherrepresent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independentlyof each another represent alkyl or cycloalkyl; or a fluorescent group;or

[0047] R¹ represents a bi-cyclic heterocyclic group composed of amonocyclic 5- or 6-membered heterocyclic group with one heteroatom,fused to a benzene ring or fused to another monocyclic 5- or 6-membered, saturated, partially saturated or unsaturated heterocyclicgroup, all of which is substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy,alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen, CF₃,OCF₃, CN, sulfanyl, amino, nitro, a mono- or polycyclic aryl group, amonocyclic 5- or 6- membered, saturated, partially saturated orunsaturated heterocyclic group, and a group of the formula—X—R′(—Y—R″)_(n); wherein X and Y independently of each anotherrepresent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independentlyof each another represent alkyl or cycloalkyl; or a fluorescent group.

[0048] In a preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

[0049] R¹ represents a 1-naphthyl group, a 2-naphthyl group, a3-naphthyl group or a 4-naphthyl group; which naphthyl groups may besubstituted one or more times at the 5, 6, 7 or 8-positions.

[0050] In a more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

[0051] R represents hydrogen or alkyl; and

[0052] R¹ represents a 1-naphthyl group or a 2-naphthyl group; whichnaphthyl groups may be substituted one or more times with substituentsselected from the group consisting of halogen, amino, hydroxy, alkoxy,alkoxy-alkoxy, alkoxy-alkyl, alkylcarbonyloxy, sulfanyl, alkylsulfanyl,alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, alkylsulfanyl-alkylsulfanyl,pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl.

[0053] In a yet more preferred embodiment the compound of the inventionis represented by the general formula (I) wherein

[0054] R¹ represents acetoxy-naphthyl, methoxy-naphthyl,hydroxy-naphthyl, bromo-naphthyl, methoxymethoxy-naphthyl,methoxyethoxy-naphthyl, ethylsulfanyl-naphthyl, methylsulfanyl-naphthyl,ethoxy-naphthyl, sulfanyl-naphthyl, methoxyethylsulfanyl-naphthyl,ethoxyethoxy-naphthyl, amino-naphthyl, dimethylamino-naphthyl,diethylamino-naphthyl, pyrrolidinyl-naphthyl, piperidinyl-naphthyl,piperazinyl-naphthyl, or homopiperazinyl-naphthyl.

[0055] In a most preferred embodiment the compound of the invention is

[0056] (±)-3-[1-(2-Iodophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0057] (±)-3-[1-(2-Bromophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0058] (±)-3-[1-(2-Chlorophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0059] (±)-3-[1-(2-iodophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0060] (±)-3-[1-(2-bromophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0061] (±)-3-[1-(2-chlorophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0062](±)-3-[6-(methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0063](±)-3-[6-(hydroxy)-2naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0064](±)-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0065]Exo-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;

[0066](±)-3-[6-(acetyloxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0067](±)-8-methyl-3-[6-(ethylsulfanyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0068](±)-8-methyl-3-[6-(methylsulfanyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0069](±)-3-[6-(ethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0070](±)-3-[6-(sulfanyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0071](±)-3-[6-(2-methoxyethylsulfanyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0072](±)-3-[6-(2-ethoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0073] (±)-3-[6-bromo-2naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0074] (±)-3-[6-amino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0075](±)-3-[6-dimethylamino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0076](±)-3-[6-diethylamino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0077](±)-8-methyl-3-[6-(N-pyrrolidinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0078](±)-8-methyl-3-[6-(N-piperidinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0079](±)-8-methyl-3-[6-(N-piperazinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0080](±)-3-[6-(N-homopiperazinyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0081] Exo-3-[6-(2-methoxyethoxy)-2naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;

[0082] Exo-3-[6-methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;

[0083] (±)-3-[6-Isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0084] (±)-3-[6-Quinolinyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0085] (±)-3-[7-Isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0086] (±)-3-[7-Quinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0087](±)-3-[1-H-5-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0088](±)-3-[1-H-6-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0089](±)-3-[1-H-5-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0090](±)-3-[1-H-6-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0091](±)-3-[2-Amino-1-H-5-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0092](±)-3-[2-Amino-1-H-6-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0093] (±)-3-[6-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0094] (±)-3-[6-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0095] (±)-3-[6-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0096] (±)-3-7-Bromo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0097] (±)-3-[7-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0098] (±)-3-[7-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0099] (±)-3-[7-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0100] (±)-3-[6-phthalazinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0101] (±)-3-[5-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0102] (±)-3-[6-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0103] (±)-3-[5-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0104] (±)-3-[6-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0105] (±)-3-[5-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0106] (±)-3-[6-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0107] (±)-3-[1-Methyl-5-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0108] (±)-3-[1-Methyl-6-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0109] (±)-3-[5-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0110] (±)-3-[6-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0111](±)-3-[2-Methyl-5-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0112](±)-3-[2-Methyl-6-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0113](±)-3-[1-Methyl-5-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0114](±)-3-[1-Methyl-6-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0115] (±)-3-[6-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0116] (±)-3-[7-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0117] (±)-3-[6-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0118] (±)-3-[7-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0119] (±)-3-[6-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or

[0120] (±)-3-[7-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0121] in their labelled or unlabelled form;

[0122] or a pharmaceutically acceptable addition salt thereof.

[0123] In another embodiment preferred embodiment the compound of theinvention represented by the general formula (I) wherein

[0124] R¹ represents a monocyclic 5- or 6-membered heterocyclic group,which heterocyclic group may be un-saturated, partially un-saturated orsaturated, and may contain one or two heteroatoms selected from thegroup consisting of N, S, O and Se.

[0125] In a more preferred embodiment the compound of the invention isrepresented by the general formula (I) wherein

[0126] R¹ represents a 5-membered heterocyclic group selected from thegroup consisting of dioxolanyl, furanyl, furazanyl, imidazolyl,isoimidazolyl, isopyrrolyl, isothiazolyl, isoxazolyl, oxazolyl,pyrazolyl, pyrrolyl, pyrrolidinyl, selenophene-yl, thiadiazolyl,thiazolyl, thienyl, and triazolyl.

[0127] In a yet more preferred embodiment the compound of the inventionis represented by the general formula (I) wherein

[0128] R¹ represents a 5-membered heterocyclic group selected from thegroup consisting of 2-furanyl, 2-thienyl, 4-thiazolyl, 5-imidazolyl,5-triazolyl, 2-pyrrolyl, 2-selenophene-yl, 3-thiadiazolyl, 5-isoxazolyl,5-oxazolyl, 5-pyrazolyl, 5-isothiazolyl, 5-furazanyl; which heterocyclicgroups may be substituted one or more times with substituents selectedfrom the group consisting halogen, amino, hydroxy, alkoxy,alkoxy-alkoxy, alkoxy-alkyl, sulfanyl, alkylsulfanyl,alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, andalkylsulfanyl-alkylsulfanyl.

[0129] In an even more preferred embodiment the compound of theinvention is represented by the general formula (I) wherein

[0130] R¹ represents a 6-membered heterocyclic group selected from thegroup consisting of dioxanyl, morpholinyl, oxazinyl, piperazinyl,piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyridinyl, andpyrimidinyl.

[0131] In a still more preferred embodiment the compound of theinvention is represented by the general formula (I) wherein

[0132] R¹ represents a 6-membered heterocyclic group selected from thegroup consisting of 3-pyridyl, 4-pyridazyl, 4-pyrimidyl, and3-pyrazinyl; which heterocyclic groups may be substituted one or moretimes with substituents selected from the group consisting halogen,amino, hydroxy, alkoxy, alkoxy-alkoxy, alkoxy-alkyl, sulfanyl,alkylsulfanyl, alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, andalkylsulfanyl-alkylsulfanyl.

[0133] In an even more preferred embodiment the compound of theinvention is represented by the general formula (I) wherein

[0134] R¹ represents a bi-cyclic heterocyclic group selected from thegroup consisting of 5 or 6-benzimidazolyl, 5 or 6-benzofuranyl, 5 or6-benzothiazolyl, 5 or 6-benzothienyl, 5 or 6-benzotrizolyl, 6 or7-cinnolinyl, 5 or 6-indazolyl, 5 or 6-indolizinyl, 5 or 6-indolyl, 5 or6-isoindolyl, 6 or 7-isoquinolinyl, 6-phthalazinyl, 6 or 7-quinolinyl, 6or 7-quinolizinyl, and 6 or 7-quinoxalinyl; which heterocyclic groupsmay be substituted one or more times with substituents selected from thegroup consisting halogen, amino, hydroxy, alkoxy, alkoxy-alkyl,alkoxy-alkoxy, sulfanyl, alkylsulfanyl, alkylsulfanyl-alkoxy,alkoxy-alkylsulfanyl, and alkylsulfanyl-alkylsulfanyl.

[0135] In a most preferred embodiment the compound of the invention is

[0136] (±)-3-[2-(3-Bromofuranyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene;

[0137] (±)-3-[2-(3-Bromofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0138] (±)-3-[2-(3-Bromofuranyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;

[0139](±)-3-[2-(3-Chlorofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0140] (±)-3-[2-(3-Iodofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0141] (±)-3-[2-(3-Bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0142] (±)-3-[2-(3-Bromothienyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;

[0143] (±)-3-[2-(3-Bromothienyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene;

[0144] (±)-3-[2-(3-Iodoothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0145](±)-3-[2-(3,4-Dibromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0146](±)-3-[2-(3,4-Dichlorothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0147](±)-3-[4-(5-Bromothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0148](±)-3-[4-(5-Chlorothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0149](±)-3-[4-(5-Iodothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0150](±)-3-[5-(4-Bromo-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0151](±)-3-[5-(4-Chloro-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0152](±)-3-[5-(4-Iodo-1-methyl-imidzolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0153](±)-3-[5-(4-Bromo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0154](±)-3-[5-(4-Chloro-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0155](±)-3-[5-(4-Iodo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0156](±)-3-[2-(3-Bromo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0157](±)-3-[2-(3-Chloro-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0158](±)-3-[2-(3-Iodo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0159](±)-3-[2-(3-Bromoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0160](±)-3-[2-(3-Chloroselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0161](±)-3-[2-(3-Iodoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0162](±)-3-[3-(4-Bromo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0163](±)-3-[3-(4-Chloro-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0164](±)-3-[3-(4-Iodo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0165](±)-3-[5-(4-Bromo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0166](±)-3-[5-(4-Chloro-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0167](±)-3-[5-(4-Iodo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0168](±)-3-[5-(4-Bromo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0169](±)-3-[5-(4-Chloro-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0170](±)-3-[5-(4-Iodo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0171](±)-3-[5-(4-Bromo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0172](±)-3-[5-(4-Chloro-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0173](±)-3-[5-(4-Iodo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0174](±)-3-[5-(4-Bromo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0175](±)-3-[5-(4-Chloro-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0176](±)-3-[5-(4-Iodo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0177](±)-3-[5-(4-Bromo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0178](±)-3-[5-(4-Chloro-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0179](±)-3-[5-(4-Iodo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0180](±)-3-[3-(2-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0181](±)-3-[3-(2-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0182](±)-3-[3-(4-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0183](±)-3-[3-(4-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0184](±)-3-[4-(3-Bromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0185](±)-3-[4-(3-Chloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0186](±)-3-[4-(3,6-Dibromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0187](±)-3-[4-(3,6-Dichloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0188](±)-3-[4-(5-Bromo-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0189](±)-3-[4-(5-Chloro-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0190](±)-3-[3-(2,6-dichloropyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;or

[0191](±)-3-[3-(2-Chloro-pyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0192] in labelled or unlabelled form;

[0193] or a pharmaceutically acceptable addition salt thereof.

Definition of Substituents

[0194] In the context of this invention halogen represents a fluorine, achlorine, a bromine or an iodine atom.

[0195] In the context of this invention an alkyl group designates aunivalent saturated, straight or branched hydrocarbon chain. Thehydrocarbon chain preferably contain of from one to eighteen carbonatoms (C₁₋₁₈-alkyl), more preferred of from one to six carbon atoms(C₁₋₆-alkyl; lower alkyl), including pentyl, isopentyl, neopentyl,tertiary pentyl, hexyl and isohexyl. In a preferred embodiment alkylrepresents a C₁₋₄-alkyl group, including butyl, isobutyl, secondarybutyl, and tertiary butyl. In a preferred embodiment of this inventionalkyl represents a C₁₋₃-alkyl group, which may in particular be methyl,ethyl, propyl or isopropyl.

[0196] In the context of this invention a cycloalkyl group designates acyclic alkyl group, preferably containing of from three to seven carbonatoms (C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl.

[0197] In the context of this invention an alkenyl group designates acarbon chain containing one or more double bonds, including di-enes,tri-enes and poly-enes. In a preferred embodiment the alkenyl group ofthe invention comprises of from two to six carbon atoms (C₂₋₆-alkenyl),including at least one double bond. In a most preferred embodiment thealkenyl group of the invention is ethenyl; 1,2- or 2,3-propenyl; or1,2-, 2,3-, or 3,4-butenyl.

[0198] In the context of this invention an alkynyl group designates acarbon chain containing one or more triple bonds, including di-ynes,tri-ynes and poly-ynes. In a preferred embodiment the alkynyl group ofthe invention comprises of from two to six carbon atoms (C₂₋₆-alkynyl),including at least one triple bond. In its most preferred embodiment thealkynyl group of the invention is ethynyl, 1,2- or 2,3-propynyl, 1,2-,2,3- or 3,4-butynyl.

[0199] In the context of this invention a cycloalkyl-alkyl groupdesignates a cycloalkyl group as defined above, which cycloalkyl groupis substituted on an alkyl group as also defined above. Examples ofpreferred cycloalkyl-alkyl groups of the invention includecyclopropylmethyl and cyclopropylethyl.

[0200] In the context of this invention an alkoxy group designates an“alkyl-O-” group, wherein alkyl is as defined above.

[0201] In the context of this invention an alkoxy-alkyl group designatesan “alkyl-O-alkyl-” group, wherein alkyl is as defined above.

[0202] In the context of this invention an alkoxy-alkoxy groupdesignates an “alkyl-O-alkyl-O-” group, wherein alkyl is as definedabove.

[0203] In the context of this invention an alkylsulfanyl designates an“alkyl-S-” group (a thio-alkoxy group), wherein alkyl is as definedabove. Likewise alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, andalkylsulfanyl-alkylsulfanyl designates an alkylsulfanyl as definedabove, attached to another alkylsulfanyl or to an alkoxy group asdefined above.

[0204] In the context of this invention an alkylcarbonyloxy groupdesignates an “alkyl-CO-O-” group, wherein alkyl is as defined above.

[0205] In the context of this invention an amino group may be a primary(—NH₂), secondary (—NH-alkyl), or tertiary (—N(alkyl)₂) amino group,i.e. it may be substituted once or twice with an alkyl group as definedabove.

[0206] In the context of this invention a mono- or polycyclic aryl groupdesignates a monocyclic or polycyclic aromatic hydrocarbon group.Examples of preferred aryl groups of the invention include phenyl,naphthyl and anthracenyl.

[0207] In the context of this invention an aralkyl group designates amono- or polycyclic aryl group as defined above, which aryl group isattached to an alkyl group as also defined above. A preferred aralkylgroup of the invention is benzyl.

[0208] In the context of this invention an aryloxy group designates an“aryl-O-” group, wherein aryl is a mono- or polycyclic aryl group asdefined above.

[0209] In the context of this invention a fluorescent group is afunctional group which can be detected by spectroscopic methods and maybe selected from the group of naturally occurring fluorophores orchemically synthesized fluorescent groups, such as rhodamine, greenfluorescent protein or fluorescein and its derivatives.

[0210] In the context of this invention a monocyclic 5- or 6-memberedheterocyclic group is a monocyclic compound holding one or moreheteroatoms in its ring structure. Preferred heteroatoms includenitrogen (N), oxygen (O), sulphur (S) and selen (Se). The ring structuremay in particular be aromatic (i.e. a heteroaryl), unsaturated orpartially unsaturated.

[0211] Examples of preferred heterocyclic aromatic monocyclic groups ofthe invention include 1,3,2,4- or 1,3,4,5-dioxadiazolyl, dioxatriazinyl,dioxazinyl, 1,2,3-, 1,2,4-, 1,3,2- or 1,3,4-dioxazolyl, 1,3,2,4- or1,3,4,5-dithiadiazolyl, dithiatriazinyl, dithiazinyl, 1,2,3-dithiazolyl,2- or 3-furanyl, furazanyl, 1,2 or 4-imidazolyl, isoindazolyl,isothiazol-3,4 or 5-yl, isoxazol-3,4 or 5-yl, 1,2,3-, 1,2,4-, 1,2,5- or1,3,4-oxadiazol-3,4 or 5-yl, oxatetrazinyl, oxatriazinyl, 1,2,3,4- or1,2,3,5-oxatriazolyl, oxazol-2,4 or 5-yl, 2 or 3-pyrazinyl, 1,3 or4-pyrazolyl, 3 or 4-pyridazinyl, 2,3 or 4-pyridinyl, 2,4 or5-pyrimidinyl, 1,2 or 3-pyrrolyl (azolyl), 1,2,3,4- or2,1,3,4-tetrazolyl, thiadiazol-3,4 or 5-yl, thiazol-2,4 or 5-yl, 2 or3-thienyl, 1,2,3-, 1,2,4- or 1,3,5-triazinyl, and 1,2,3-, 1,2,4-, 2,1,3-or 4,1,2-triazolyl.

[0212] Examples of preferred saturated or partially saturatedheterocyclic monocyclic groups of the invention include1,3,5,6,2-dioxadiazinyl, 1,2,3,4,5-, 1,2,3,5,4-dioxadiazolyl, dioxanyl,1,3-dioxolyl, 1,3,5,6,2-dithiadiazinyl, 1,2,3,4,5- or1,2,3,5,4-dithiadiazolyl, 2-isoimidazolyl, isopyrrolyl, isotetrazolyl,1,2,3- or 1,2,4-isotriazolyl, morpholinyl, oxadiazinyl, 1,2,4-, 1,2,6-,1,3,2-, 1,3,6- or 1,4,2-oxazinyl, piperazinyl, homopiperazinyl,piperidinyl, 1,2-, 1,3- or 1,4-pyranyl, and 1,2,3-pyrrolidinyl.

[0213] In the context of this invention a bicyclic heteroaryl groupcomposed of a 5 to 6 membered monocyclic heteroaryl group and a fusedbenzene ring or another 5 to 6 membered monocyclic heteroaryl groupdesignates a monocyclic 5 to 6 membered heteroaryl group as definedabove, which group is fused to a benzene ring or fused to another 5 to 6membered heteroaryl group as defined above.

[0214] Examples of preferred bicyclic heteroaryl groups of the inventioninclude 3,4,5,6 or 7-anthranilyl, 2,4,5 or 6-benzimidazolyl,1,3-benzisodiazol-2,4,5,6 or 7-yl, 1,2-benzisothianin-3,4,5,6,7 or 8-yl,1,4-benzisothiazin-2,3,5,6,7 or 8-yl, 2,3,4,5,6 or 7-benzofuranyl,2,3,4,5,6,7 or 8-benzopyranyl, 1,3,2-, 1,4,2-, 2,3,1- or3,1,4-benzoxazinyl, 2,3,4,5,6 or 7-benzofuranyl, 1,3,4,5,6 or7-isobenzofuranyl, 1,2- or 1,4-benzopyranyl, 2,4,5,6 or7-benzothiazolyl, 5 or 6-benzothienyl, 5 or 6-benzotrizolyl, 2,3,4,5,6,7or 8-chromanyl, 4H-chromenyl, 3,4,5,6,7 or 8-cinnolinyl, 2,3,4,5,6 or7-indanyl, 3,4,5,6 or 7-indazolyl, 5 or 6-indolizinyl, 2,3,4,5,6 or7-indolyl, 1,3,4,5,6 or 7-isoindolyl, 2,3,4,5,6,7 or 8-quinolinyl,1,3,4,5,6,7 or 8-isoquinolinyl, 1,4,5,6,7 or 8-phthalazinyl,thieno[3.2-b]thienyl, and thieno[2.3-b]thienyl,1,4,5,6,7,8-phthalazinyl, 2,4,5,6,7,8-quinazolinyl, 6 or 7-quinolinyl, 6or 7-quinolizinyl, and 2,3,5,6,7,8-quinoxalinyl.

[0215] The compounds of the invention may be labelled or unlabelled. Intheir labelled form they may be labelled by incorporation of a isotopeinto the molecule. In the context of this invention an isotope of acompound means that one or more atom in the compound is substituted withan isotope of the naturally occurring atoms including deuterium,tritium, ¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F. The isotope incorporationmay be measured by conventional scintillation counting techniques.

Steric Isomers

[0216] The chemical compounds of the present invention may exist in (+)and (−) forms as well as in racemic forms. The racemates of theseisomers and the individual isomers themselves are within the scope ofthe present invention.

[0217] Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or I- (tartrates, mandelates,or camphorsulphonate) salts for example.

[0218] The chemical compounds of the present invention may also beresolved by the formation of diastereomeric amides by reaction of thechemical compounds of the present invention with an optically activeactivated carboxylic acid such as that derived from (+) or (−)phenylalanine, (+) or (−) phenylglycine, (+) or (−) camphanic acid or bythe formation of diastereomeric carbamates by reaction of the chemicalcompound of the present invention with an optically active chloroformateor the like.

[0219] Additional methods for the resolving the optical isomers areknown in the art. Such methods include those described by Jaques J.Collet A, & Wilen S in “Enantiomers, Racemates, and Resolutions”, JohnWiley and Sons, New York (1981).

[0220] Optical active compounds can also be prepared from optical activestarting materials.

Pharmaceutically Acceptable Salts

[0221] The chemical compound of the invention may be provided in anyform suitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

[0222] Examples of pharmaceutically acceptable addition salts include,without limitation, the non-toxic inorganic and organic acid additionsalts such as the hydrochloride derived from hydrochloric acid, thehydrobromide derived from hydrobromic acid, the nitrate derived fromnitric acid, the perchlorate derived from perchloric acid, the phosphatederived from phosphoric acid, the sulphate derived from sulphuric acid,the formate derived from formic acid, the acetate derived from aceticacid, the aconate derived from aconitic acid, the ascorbate derived fromascorbic acid, the benzenesulfonate derived from benzensulfonic acid,the benzoate derived from benzoic acid, the cinnamate derived fromcinnamic acid, the citrate derived from citric acid, the embonatederived from embonic acid, the enantate derived from enanthic acid, thefumarate derived from fumaric acid, the glutamate derived from glutamicacid, the glycolate derived from glycolic acid, the lactate derived fromlactic acid, the maleate derived from maleic acid, the malonate derivedfrom malonic acid, the mandelate derived from mandelic acid, themethanesulfonate derived from methane sulphonic acid, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, thephthalate derived from phthalic acid, the salicylate derived fromsalicylic acid, the sorbate derived from sorbic acid, the stearatederived from stearic acid, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulfonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

[0223] Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

[0224] Metal salts of a chemical compound of the invention includesalkali metal salts, such as the sodium salt of a chemical compound ofthe invention containing a carboxy group.

[0225] The chemical compound of the invention may be provided indissoluble or indissoluble forms together with a pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Dissolubleforms may also include hydrated forms such as the monohydrate, thedihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and thelike. In general, the dissoluble forms are considered equivalent toindissoluble forms for the purposes of this invention.

Method of Producing the Compounds

[0226] The compounds of the invention may be prepared by anyconventional method useful for the preparation of analogous compoundsand as described in the examples below.

[0227] Starting materials for the processes described in the presentpatent application are known or can be prepared by known processes fromcommercially available materials.

[0228] A compound of the invention can be converted to another compoundof the invention using conventional methods.

[0229] In a preferred embodiment, the compounds of the invention may beprepared the following method, which method comprises:

[0230] A) the step of reacting a compound having the formula

[0231] wherein R is as defined herein, with a compound of the formulaR¹—Li,

[0232] wherein R¹ is as defined herein, followed by dehydration of thecompound obtained; or

[0233] B) the step of reacting a compound having the formula

[0234] wherein R is as defined herein, with a compound of formula R¹—X,

[0235] wherein R¹ is as defined herein,

[0236] and X represents halogen, boronic acid, or trialkylstannyl; or

[0237] C) the step of reducing a compound having the formula

[0238] wherein R¹ is as defined herein.

[0239] The products of the reactions described herein are isolated byconventional means such as extraction, crystallisation, distillation,chromatography, and the like.

Biological Activity

[0240] The compounds of the present invention have proven to benicotinic receptor modulators. In the context of this invention the term“modulator” covers agonists, partial agonists, antagonists andallosteric modulators of the nicotinic acetyl choline receptor (nAChR).

[0241] The compounds of the present invention exhibit a nicotinicpharmacology at least as good as nicotine itself, but preferably withlesser or even without the side effects associated with the use ofnicotine. Moreover, the compounds of the invention are believed to havethe potential as enhancers of neurotransmitter secretion, and suppresssymptoms associated with a low activity of neurotransmitters.

[0242] The compounds of the present invention may in particular becharacterised by having one or more of the following functionalities: Ahigh binding selectivity for the receptor subtypes of neuronal nAChR's,in particular the α3 and/or the α7 subtype, binding selectivity for theserotonin receptor, a low affinity for the muscular subtype, aninduction of cell survival, an oral efficacy in vivo ofarousal/attention, a low toxicity in vivo, and by being non-mutagenic.

[0243] Due to their pharmacological profile the compounds of theinvention may be useful for the treatment of diseases or conditions asdiverse as CNS related diseases, diseases related to smooth musclecontraction, endocrine disorders, diseases related to neurodegeneration,diseases related to inflammation, pain, and withdrawal symptoms causedby the termination of abuse of chemical substances.

[0244] In a preferred embodiment the compounds of the invention are usedfor the treatment of diseases, disorders, or conditions relating to thecentral nervous system. Such diseases or disorders includes anxiety,cognitive disorders, learning deficit, memory deficits and dysfunction,Alzheimer's disease, attention deficit, attention deficit hyperactivitydisorder, Parkinson's disease, Huntington's disease, Amyotrophic LateralSclerosis, Gilles de la Tourettes syndrome, depression, mania, manicdepression, schizophrenia, obsessive compulsive disorders (OCD), panicdisorders, eating disorders such as anorexia nervosa, bulimia andobesity, narcolepsy, nociception, AIDS-dementia, senile dementia,periferic neuropathy, autism, dyslexia, tardive dyskinesia,hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia,chronic fatigue syndrome, sleeping disorders, pseudodementia, Ganser'ssyndrome, pre-menstrual syndrome, late luteal phase syndrome, chronicfatigue syndrome, mutism, trichotillomania, and jetlag.

[0245] In another preferred embodiment the compounds of the inventionmay be useful for the treatment of diseases, disorders, or conditionsassociated with smooth muscle contractions, including convulsivedisorders, angina pectoris, premature labor, convulsions, diarrhoea,asthma, epilepsy, tardive dyskinesia, hyperkinesia, prematureejaculation, and erectile difficulty.

[0246] In yet another preferred embodiment the compounds of theinvention may be useful for the treatment of endocrine disorders, suchas thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

[0247] In still another preferred embodiment the compounds of theinvention may be useful for the treatment of neurodegenerativedisorders, including transient anoxia and induced neurodegeneration.

[0248] In even another preferred embodiment the compounds of theinvention may be useful for the treatment of inflammatory diseases,disorders, or conditions, including inflammatory skin disorders such asacne and rosacea, Chron's disease, inflammatory bowel disease,ulcerative collitis, and diarrhoea.

[0249] In still another preferred embodiment the compounds of theinvention may be useful for the treatment of mild, moderate or evensevere pain of acute, chronic or recurrent character, as well as paincaused by migraine, postoperative pain, and phantom limb pain.

[0250] Finally the compounds of the invention may be useful for thetreatment of withdrawal symptoms caused by termination of use ofaddictive substances. Such addictive substances include nicotinecontaining products such as tobacco, opioids such as heroin, cocaine andmorphine, benzodiazepines and benzodiazepin-like drugs, and alcohol.Withdrawal from addictive substances is in general a traumaticexperience characterised by anxiety and frustration, anger, anxiety,difficulties in concentrating, restlessness, decreased heart rate andincreased appetite and weight gain.

[0251] In this context “treatment” covers treatment, prevention,prophylaxis and alleviation of withdrawal symptoms and abstinence aswell as treatment resulting in a voluntary diminished intake of theaddictive substance.

Neuroimaging

[0252] The 8-azabicyclo[3.2.1]oct-2-ene and -octane derivatives of theinvention, in particular those being selective for the nicotinicreceptor subtype α3, may be useful as diagnostic tools or monitoringagents in various diagnostic methods, and in particular for in vivoreceptor imaging (neuroimaging).

[0253] In another aspect of the invention a method for the non-invasivedetermination of the distribution of a tracer compound inside a whole,intact living animal or human body using a physical detection method isprovided. According to this method a tracer compound is a compound ofthe invention, or any of its enantiomers or any mixture thereof, or apharmaceutically acceptable salt thereof, in labelled or unlabelledform.

[0254] In a preferred embodiment the physical detection method isselected from PET, SPECT; MRS, MRI, CAT, or combinations thereof.

[0255] The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention “label” stands for thebinding of a marker to the compound of interest that will allow easyquantitative detection of said compound.

[0256] The labelled compound of the invention preferably contains atleast one radionuclide as a label. Positron emitting radionuclides areall candidates for usage. In the context of this invention theradionuclide is preferably selected from ¹¹C, ¹⁸F, ¹⁵O, ¹³N, 123I, ¹²⁵I,¹³¹I, ³H and ^(99m)Tc.

[0257] An examples of commercially available labelling agents, which canbe used in the preparation of the labelled compounds of the presentinvention is [¹¹C]O₂, ¹⁸F, and NaI with different isotopes of Iodine.

[0258] In particular [C¹¹]O₂ may be converted to a [¹¹C]-methylatingagent, such as [¹¹C]H₃I or [¹¹C]-methyl triflate.

[0259] Labelled compounds containing e.g. [¹²⁵I] labelled1-iodoprop-1-en-3-yl as substituent on N-8 may be prepared as describedin the art [Elmaleh, et al.; J. Nucl. Med. 1996 37 1197-1202].

[0260] Labelled compounds containing e.g. [¹⁸F]-alkyl substituted N-8may be prepared as described in the art, e.g. in WO 96/39198.

[0261] The tracer compound can be selected in accordance with thedetection method chosen.

[0262] In one preferred embodiment, the labelled or unlabelled compoundof the invention can be detected by a suitable spectroscopic method, inparticular UV spectroscopy and/or fluorescence spectroscopy.

[0263] In anther preferred embodiment, the compounds of the inventionlabelled by incorporation of a isotope into the molecule, which may inparticular be an isotope of the naturally occurring atoms includingdeuterium, tritium, ¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F, the isotopeincorporation may be measured by conventional scintillation countingtechniques.

[0264] In a third preferred embodiment, the physical method fordetecting said tracer compound of the present invention is selected fromPosition Emission Tomography (PET), Single Photon Imaging ComputedTomography (SPECT), Magnetic Resonance Spectroscopy (MRS), MagneticResonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), orcombinations thereof.

[0265] Before conducting the method of the present invention, adiagnostically effective amount of a labelled or unlabelled compound ofthe invention is administered to a living body, including a human.

[0266] The diagnostically effective amount of the labelled or unlabelledcompound of the invention to be administered before conducting thein-vivo method for the present invention is within a range of from 0.1ng to 100 mg per kg body weight, preferably within a range of from 1 ngto 10 mg per kg body weight.

Pharmaceutical Compositions

[0267] In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

[0268] While a chemical compound of the invention for use in therapy maybe administered in the form of the raw chemical compound, it ispreferred to introduce the active ingredient, optionally in the form ofa physiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers and/ordiluents.

[0269] In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefor and,optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

[0270] Pharmaceutical compositions of the invention may be thosesuitable for oral, rectal, nasal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (includingintramuscular, sub-cutaneous and intravenous) administration, or thosein a form suitable for administration by inhalation or insufflation.

[0271] The chemical compound of the invention, together with aconventional adjuvant, carrier, or diluent, may thus be placed into theform of pharmaceutical compositions and unit dosages thereof, and insuch form may be employed as solids, such as tablets or filled capsules,or liquids such as solutions, suspensions, emulsions, elixirs, orcapsules filled with the same, all for oral use, in the form ofsuppositories for rectal administration; or in the form of sterileinjectable solutions for parenteral (including subcutaneous) use. Suchpharmaceutical compositions and unit dosage forms thereof may compriseconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and such unit dosage formsmay contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.

[0272] The chemical compound of the present invention can beadministered in a wide variety of oral and parenteral dosage forms. Itwill be obvious to those skilled in the art that the following dosageforms may comprise, as the active component, either a chemical compoundof the invention or a pharmaceutically acceptable salt of a chemicalcompound of the invention.

[0273] For preparing pharmaceutical compositions from a chemicalcompound of the present invention, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

[0274] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component.

[0275] In tablets, the active component is mixed with the carrier havingthe necessary binding capacity in suitable proportions and compacted inthe shape and size desired.

[0276] The powders and tablets preferably contain from five or ten toabout seventy percent of the active compound. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

[0277] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

[0278] Compositions suitable for vaginal administration may be presentedas pessaries, tampons, creams, gels, pastes, foams or sprays containingin addition to the active ingredient such carriers as are known in theart to be appropriate.

[0279] Liquid preparations include solutions, suspensions, andemulsions, for example, water or water-propylene glycol solutions. Forexample, parenteral injection liquid preparations can be formulated assolutions in aqueous polyethylene glycol solution.

[0280] The chemical compound according to the present invention may thusbe formulated for parenteral administration (e.g. by injection, forexample bolus injection or continuous infusion) and may be presented inunit dose form in ampoules, pre-filled syringes, small volume infusionor in multi-dose containers with an added preservative. The compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form., obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0281] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavours, stabilising and thickening agents, as desired.

[0282] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, or other well known suspending agents.

[0283] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0284] For topical administration to the epidermis the chemical compoundaccording to the invention may be formulated as ointments, creams orlotions, or as a transdermal patch. Ointments and creams may, forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents. Lotions may be formulatedwith an aqueous or oily base and will in general also contain one ormore emulsifying agents, stabilising agents, dispersing agents,suspending agents, thickening agents, or colouring agents.

[0285] Compositions suitable for topical administration in the mouthinclude lozenges comprising the active agent in a flavoured base,usually sucrose and acacia or tragacanth; pastilles comprising theactive ingredient in an inert base such as gelatin and glycerine orsucrose and acacia; and mouthwashes comprising the active ingredient ina suitable liquid carrier.

[0286] Solutions or suspensions are applied directly to the nasal cavityby conventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

[0287] Administration to the respiratory tract may also be achieved bymeans of an aerosol formulation in which the active ingredient isprovided in a pressurised pack with a suitable propellant such as achlorofluorocarbon (CFC) for example dichlorodifluoromethane,trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, orother suitable gas. The aerosol may conveniently also contain asurfactant such as lecithin. The dose of drug may be controlled byprovision of a metered valve.

[0288] Alternatively the active ingredients may be provided in the formof a dry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

[0289] In compositions intended for administration to the respiratorytract, including intranasal compositions, the compound will generallyhave a small particle size for example of the order of 5 microns orless. Such a particle size may be obtained by means known in the art,for example by micronization.

[0290] When desired, compositions adapted to give sustained release ofthe active ingredient may be employed.

[0291] The pharmaceutical preparations are preferably in unit dosageforms. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packaged tablets, capsules,and powders in vials or ampoules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

[0292] Tablets or capsules for oral administration and liquids forintravenous administration and continuous infusion are preferredcompositions.

[0293] The dose administered must of course be carefully adjusted to theage, weight and condition of the individual being treated, as well asthe route of administration, dosage form and regimen, and the resultdesired. It is presently contemplated that compositions containing offrom about 0.1 to about 500 mg of active ingredient per unit dosage,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

[0294] A satisfactory result can, in certain instances, be obtained at adosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit ofthe dosage range is about 10 mg/kg i.v. and 100 mg/kg p.o. Preferredranges are from about 0.001 to about 1 mg/kg i.v. and from about 0.1 toabout 10 mg/kg p.o.

Methods of Therapy

[0295] The compounds of the present invention are valuable nicotinic AChreceptor modulators and therefore useful for the treatment of a range ofailments involving cholinergic dysfunction as well as a range ofdisorders responsive to the action of nicotinic ACh receptor modulatorsas well as the serotonin receptor.

[0296] In another aspect the invention relates to the a method of thetreatment or alleviation of a disease, disorder or condition of a livinganimal body, including a human, which disease, disorder or condition isresponsive to the action of a nicotinic Acetyl Choline Receptor (nAChR)modulator, which method comprises the step of administering to such aliving animal body, including a human, in need thereof a therapeuticallyeffective amount of the chemical compound of the invention.

[0297] In the context of this invention the term “treating” coverstreatment, prevention, prophylaxis or alleviation, and the term“disease” covers illnesses, diseases, disorders and conditions relatedto the disease in question.

[0298] In a preferred embodiment the disease or disorder to be treatedis a disease or disorder of the central nervous system, a disease ordisorder caused by or related to smooth muscle contraction, an endocrinedisorder, a disease or disorder caused by or related toneuro-degeneration, a disease or disorder caused by or related toinflammation, pain, a withdrawal symptom caused by the termination ofabuse of chemical substances.

[0299] In a more preferred embodiment the disease or disorder of thecentral nervous system is anxiety, cognitive disorders, learningdeficit, memory deficits and dysfunction, Alzheimer's disease, attentiondeficit, attention deficit hyperactivity disorder, Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles de laTourettes syndrome, depression, mania, manic depression, schizophrenia,obsessive compulsive disorders (OCD), panic disorders, eating disorderssuch as anorexia nervosa, bulimia and obesity, narcolepsy, nociception,AIDS-dementia, senile dementia, periferic neuropathy, autism, dyslexia,tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumaticsyndrome, social phobia, chronic fatigue syndrome, sleeping disorders,pseudodementia, Ganser's syndrome, pre-menstrual syndrome, late lutealphase syndrome, chronic fatigue syndrome, mutism, trichotillomania, andjetlag

[0300] In another preferred embodiment the disease or disorder caused byor related to smooth muscle contraction is convulsive disorders, anginapectoris, premature labor, convulsions, diarrhoea, asthma, epilepsy,tardive dyskinesia, hyperkinesia, premature ejaculation, and erectiledifficulty.

[0301] In a third preferred embodiment the endocrine disorder isthyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

[0302] In a fourth preferred embodiment the neuro-degenerative diseaseis transient anoxia and induced neurodegeneration.

[0303] In a fifth preferred embodiment the disease or disorder caused byor related to inflammation is an inflammatory skin disorder such as acneand rosacea, Chron's disease, inflammatory bowel disease, ulcerativecollitis, and diarrhoea.

[0304] In a sixth preferred embodiment pain is a mild, a moderate or asevere pain of acute, chronic or recurrent character, a pain caused bymigraine, a postoperative pain, or a phantom limb pain.

[0305] In a third preferred embodiment the addictive substance is anicotine containing product such as tobacco, an opioids such as heroin,cocaine or morphine, a benzodiazepine or a benzodiazepin-like drug, oralcohol.

[0306] It is at present contemplated that a suitable dosage lies withinthe range of from about 0.1 to about 500 milligram of active substancedaily, more preferred of from about 10 to about 70 milligram of activesubstance daily, administered once or twice a day, dependent as usualupon the exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

EXAMPLES

[0307] The invention is further illustrated with reference to thefollowing examples which are not intended to be in any way limiting tothe scope of the invention as claimed.

Example 1 Preparatory Example

[0308] General:

[0309] All reactions involving air sensitive reagents or intermediateswere performed under nitrogen and in anhydrous solvents. Magnesiumsulfate was used as drying agent in the workup-procedures and solventswere evaporated under reduced pressure.

(±)-3-[6-(Methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-enefumaric acid salt

[0310] To a solution of 2-Bromo-6-methoxynaphthalene (8.8 g, 37.1 mmol)in tetrahydrofuran (150 ml) was added: buthyllithium (17.0 ml, 40.8mmol) at −70° C. The mixture was stirred for 1 h at −70° C., followed byaddition of tropinone (5.2 g, 37.1 mmol) in tetrahydrofuran (75 ml). Themixture was stirred at −70° C. for 30 min, and was allowed to reach −20°C. Aqueous sodium hydroxide (200 m, 1 M) was added at −20° C., and themixture was allowed to reach room temperature. The mixture was extractedtwo times with diethyl ether (50 ml). The mixture was recrystalised frompetroleum ether and yielded the intermediate product endo andexo-3-hydroxy-3-[6-(methoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]octane.Yield 4.06 g, 37%.

[0311] A mixture of endo andexo-3-hydroxy-3-[6-(methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane(2.50 g, 8.4 mmol), thionyl chloride (12.5 g, 105 mmol) andtetrahydrofuran (50 ml) was stirred for 30 min at 50° C. The excess ofthionyl chloride was evaporated. Potassium hydroxide (3.8 g, 67.2 mmol)and ethanol (60 ml) were added, and the mixture stirred for 20 min. Thecrude mixture was purified by chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound as free base. The corresponding salt was obtained by additionof a diethyl ether and methanol mixture (9:1), saturated with fumaricacid. Yield 2.0 g, 60%. Mp 192.6-195.4° C.

(±)-3-[6-(Hydroxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-enefumaric acid salt

[0312] To a solution of 2-bromo-6-methoxymethoxynaphthalene (8.3 g, 28.5mmol) in tetrahydrofuran (100 ml) was added: buthyllithium (12.5 ml,31.3 mmol) at −70° C. The mixture was stirred for 1 h at −70° C.,followed by addition of tropinone (3.9 g, 28.5 mmol) in tetrahydrofuran(50 ml). The mixture was stirred at −70° C. for 30 min and was allowedto reach −20° C. Aqueous sodium hydroxide (75 ml, 1 M) was added at −20°C., and the mixture was allowed to reach room temperature. The mixturewas extracted two times with diethyl ether (75 ml). The mixture wastriturated with petroleum ether, and yielded the intermediate productendo andexo-3-hydroxy-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane.Yield 4.9 g, 53%.

[0313] A mixture of endo andexo-3-hydroxy-3-[6-(methoxymethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]octane(2.70 g, 7.9 mmol), thionyl chloride (11.8 g, 98.8 mmol) andtetrahydrofuran (50 ml) was stirred for 30 min at 50° C. The excess ofthionyl chloride was evaporated. Potassium hydroxide (3.5 g, 63.2 mmol)and ethanol (75 ml) were added, and the mixture stirred for 30 min. Thecrude mixture was purified by chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1), and gave thetitle compound as free base. The corresponding salt was obtained byaddition of a diethyl ether and methanol mixture (9:1) saturated withfumaric acid. Yield 1.4 g, 60%. Mp 191.2-194.7° C.

(±)-3-[6-(2-Methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-enefumaric acid salt

[0314] To a solution of 2-bromo-6-(2-methoxyethoxy)naphthalene (8.0 g,28.5 mmol) in tetrahydrofuran (100 ml) was added: buthyllithium (12.5ml, 31.3 mmol) at −70° C. The mixture was stirred for 1 h at −70° C.followed by addition of tropinone (3.9 g, 28.5 mmol) in tetrahydrofuran(100 ml). The mixture was stirred at −70° C. for 30 min and was allowedto reach room temperature overnight. Aqueous sodium hydroxide (100 ml,1M) was added. The mixture was extracted two times with diethyl ether(100 ml). The crude mixture was purified by chromatography on silica gelwith dichloromethane, methanol and conc. ammonia (89:10:1), and gaveendo andexo-3-hydroxy-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane.Yield 1.44 g, 15%.

[0315] A mixture of endo andexo-3-hydroxy-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane(1.3 g, 3.8 mmol), thionyl chloride (5.7 g, 47.6 mmol) andtetrahydrofuran (100 ml) was stirred for 30 min at 50° C. The excess ofthionyl chloride was evaporated. Potassium hydroxide (1.7 g, 30.4 mmol)and ethanol (20 ml) were added and the mixture stirred for 20 min. Thecrude mixture was purified by chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound as free base. The corresponding salt was obtained by additionof a diethyl ether and methanol mixture (9:1) saturated with fumaricacid. Yield 0.25 g, 15%. Mp 157.3-158.9° C.

Exo-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octanefumaric acid salt

[0316] A mixture of endo andexo3-hydroxy-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane(1.0 g, 3.1 mmol), Raney nickel (20 g, 50% in water) and ethanol (50 ml)was stirred overnight. The ethanol was separated, and the Raney nickelwas extracted two times with ethanol (25 ml). The crude mixture waspurified by chromatography on silica gel with dichloromethane, methanoland conc. ammonia (89:10:1) gave the title compound. The correspondingsalt was obtained by addition of a diethyl ether and methanol mixture(9:1) saturated with fumaric acid. Yield 20 mg, 1.5%. Mp 126.5-129.6° C.

(±)-3-[6-(Acetyloxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-enefumaric acid salt

[0317] A mixture of(±)-3-[6-(hydroxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene(0.49 mg, 1.8 mmol), acetic acid anhydride (1.9 g, 18 mmol) anddichloromethane (20 ml) was stirred at reflux for 1.5 h. The mixture wasevaporated and aqueous sodiumhydroxide (1 M, 50 ml) was added followedby extraction with ethyl acetate (2×25 ml). The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Yield 380 mg, 50%. Mp 154.2-155.6° C.

[0318] The following compounds are prepared likewise:

[0319](±)-8-Methyl-3-[6-(thioethoxy)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0320](±)-8-Methyl-3-[6-(thiomethoxy)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0321](±)-3-[6-(Ethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0322](±)-3-[6-(Mercapto)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0323](±)-3-[6-(2-Methoxythioethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0324](±)-3-[6-(2-Ethoxyethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0325] (±)-3-[6-Bromo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0326] (±)-3-[6-Amino-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0327](±)-3-[6-Dimethylamino-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0328](±)-3-[6-Diethylamino-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0329](±)-8-Methyl-3-[6-(N-pyrrolidinyl)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0330](±)-8-Methyl-3-[6-(N-piperidinyl)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0331](±)-8-Methyl-3-[6-(N-piperazinyl)-2-naphtyl]-8-azabicyclo[3.2.1]oct-2-ene;

[0332](±)-3-[6-(N-Homopiperazinyl)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0333]Exo-3-[6-(2-Methoxyethoxy)-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]octane;

[0334] Exo-3-[6-Methoxy)-2-naphtyl]-8-methyl -8-azabicyclo[3.2.1]octane;

[0335] (±)-3-[6-isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0336] (±)-3-[6-Quinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0337] (±)-3-[7-Isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0338] (±)-3-[7-Quinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0339](±)-3-[1-H-5-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0340](±)-3-[1-H-6-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0341](±)-3-[1-H-5-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0342](±)-3-[1-H-6-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0343](±)-3-[2-Amino-1-H-5-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0344](±)-3-[2-Amino-1-H-6-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0345] (±)-3-[6-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0346] (±)-3-[6-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0347] (±)-3-[6-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0348] (±)-3-[7-Bromo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0349] (±)-3-[7-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0350] (±)-3-[7-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0351] (±)-3-[7-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0352] (±)-3-[6-phthalazinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0353] (±)-3-[5-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene

[0354] (±)-3-[6-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0355] (±)-3-[5-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0356] (±)-3-[6-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0357] (±)-3-[5-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0358] (±)-3-[6-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0359] (±)-3-[1-Methyl-5-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0360] (±)-3-[1-Methyl-6-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0361] (±)-3-[5-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0362] (±)-3-[6-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0363](±)-3-[2-Methyl-5-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0364](±)-3-[2-Methyl-6-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0365](±)-3-[1-Methyl-5-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0366](±)-3-[1-Methyl-6-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0367] (±)-3-[6-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0368] (±)-3-[7-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0369] (±)-3-[6-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0370] (±)-3-[7-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0371] (±)-3-[6-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; and

[0372] (±)-3-[7-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene.

Method A(±)-3-[2-(3-Bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene fumaricacid salt

[0373] To a solution of 3-bromothiophene (25.0 g, 153.3 mmol) in THF(250 ml) was added lithiumdiisopropylamide (2 M, 168.7 mmol) at −80° C.The mixture was stirred for 1 h at −80° C. followed by addition oftropinone (21.3 g, 153.3 mmol) in THF (200 ml). The mixture was stirredat −80° C. for 1 h and was allowed to reach room temperature overnight.Sodium hydroxide (1 M, 200 ml) was added and extracted three times withdiethylether (300 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave theintermediate endo andexo-3-[3-bromo-(2-thienyl)]-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane.Yield 8.90 g, 19%.

[0374] A mixture of endo andexo-3-[3-bromo-(2-thienyl)]-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane(8.85 g, 29.3 mmol) and concentrated hydrochloric acid (100 ml) wasstirred for 2 h. The hydrochloric acid was evaporated and sodiumhydroxide (1 M, 200 ml) was added and the mixture was extracted twicewith ethyl acetate (2×100 ml). Yield 8.3 g, 100%. The corresponding saltwas obtained by addition of a diethyl ether and methanol mixture (9:1),saturated with fumaric acid. Mp 130-132° C.

(±)-3-[2-(3-Bromofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene fumaricacid salt

[0375] Was prepared according to method A. Mp 150.3-153.0° C.

Method B (±)-3-[2-(3-Bromothienyl)]-8-H-8-azabicyclo[3.2.1]oct-2-enefumaric acid salt

[0376] To a mixture of(±)-3-[2-(3-bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (4.0 g,14.1 mmol) and anhydrous xylene (40 ml) was added:2-chloroethylchloroformate (3.02 g, 21.1 mmol) at 0° C. The mixture wasstirred at reflux for 2 days. Methanol (50 ml) was added and the mixturewas heated at reflux for 2 h. The methanol was evaporated and sodiumhydroxide (60 ml, 1 M) was added. The mixture was extracted with ethylacetate (2×50 ml). The crude mixture was purified by chromatography onsilica gel with dichloromethane, methanol and conc. ammonia (89:10:1)gave the title compound. Yield 2.96 g, 78%. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Mp 184-186° C.

(±)-3-[2-(3-Bromofuranyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene fumaric acidsalt

[0377] Was prepared according to method B. Mp 176.1-176.9° C.

Method C (±)-3-[2-(3-Bromothienyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-enefumaric acid salt

[0378] A mixture of(±)-3-[2-(3-bromothienyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene (0.70 g, 2.6mmol), bromoethane (339 mg, 3.1 mmol), diisopropylethylamine (335 mg,2.6 mmol) and dimethylformamide (20 ml) was stirred at 80° C. for 4 h.Sodium hydroxide (40 ml, 1 M) was added and the mixture was extractedwith ethyl acetate (2×40 ml). The crude mixture was purified bychromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound. Yield 0.57 g (73%). Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 136-138° C.

(±)-3-[2-(3-Bromofuranyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene fumaricacid salt

[0379] Was prepared according to method C. Mp 139-141.2° C.

[0380] The following compounds are prepared likewise:

[0381] (±)-3-[2-(3-Iodoothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0382](±)-3-[2-(3-Chlorofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0383] (±)-3-[2-(3-Iodofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0384] (±)-3-[1-(2-Iodophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0385] (±)-3-[1-(2-Bromophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0386] (±)-3-[1-(2-Chlorophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0387](±)-3-[2-(3,4-Dibromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0388](±)-3-[2-(3,4-Dichlorothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0389](±)-3-[4-(5-Bromothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0390](±)-3-[4-(5-Chlorothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0391](±)-3-[4-(5-Iodothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0392](±)-3-[5-(4-Bromo-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0393](±)-3-[5-(4-Chloro-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0394](±)-3-[5-(4-Iodo-1-methyl-imidzolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0395](±)-3-[5-(4-Bromo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0396](±)-3-[5-(4-Chloro-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0397](±)-3-[5-(4-Iodo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0398](±)-3-[2-(3-Bromo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0399](±)-3-[2-(3-Chloro-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0400](±)-3-[2-(3-Iodo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0401](±)-3-[2-(3-Bromoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0402](±)-3-[2-(3-Chloroselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0403](±)-3-[2-(3-Iodoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0404](±)-3-[3-(4-Bromo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0405](±)-3-[3-(4-Chloro-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0406](±)-3-[3-(4-Iodo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0407](±)-3-[5-(4-Bromo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0408](±)-3-[5-(4-Chloro-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0409](±)-3-[5-(4-Iodo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0410](±)-3-[5-(4-Bromo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0411](±)-3-[5-(4-Chloro-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0412](±)-3-[5-(4-Iodo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0413](±)-3-[5-(4-Bromo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0414](±)-3-[5-(4-Chloro-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0415](±)-3-[5-(4-Iodo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0416](±)-3-[5-(4-Bromo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0417](±)-3-[5-(4-Chloro-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0418](±)-3-[5-(4-Iodo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0419](±)-3-[5-(4-Bromo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0420](±)-3-[5-(4-Chloro-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0421](±)-3-[5-(4-Iodo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0422](±)-3-[3-(2-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0423](±)-3-[3-(2-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0424](±)-3-[3-(4-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0425](±)-3-[3-(4-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0426](±)-3-[4-(3-Bromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0427](±)-3-[4-(3-Chloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0428](±)-3-[4-(3,6-Dibromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0429](±)-3-[4-(3,6-Dichloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0430](±)-3-[4-(5-Bromo-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0431](±)-3-[4-(5-Chloro-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;

[0432](±)-3-[3-(2,6-dichloropyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;and

[0433](±)-3-[3-(2-Chloro-pyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene.

Intermediate Preparations 2-Bromo-6-methoxynaphthalene

[0434] Sodium hydride (60%, 4.5 g, 112 mmol) was added in small portionsto a mixture of 6-bromo-2-naphthol (25.0 g, 112 mmol), iodomethane (11.8g, 168 mmol) and dimethylsulfoxide (150 ml). The mixture was stirred atroom temperature overnight. Sodium hydroxide (200 ml, 1 M) was added,and the mixture was filtered. Yield 25.1 g, 95%. Mp 76-82° C.

2-Bromo-6-methoxymethoxynaphthalene

[0435] Sodium hydride (60%, 4.5 g, 112 mmol) was added in small portionsto a mixture of 6-bromo-2-naphthol (25.0 g, 112 mmol),bromomethylmethylether (21.0 g, 168 mmol) and dimethylformamide (150ml). The mixture was stirred at room temperature for 1 h. Sodiumhydroxide (200 ml, 1 M) was added and the mixture was extracted withdiethyl ether. The product was purified chromatographically, usingdichloromethane as solvent. Yield 15.7 g, 52%. Mp 46.8-49.2° C.

2-Bromo-6-methoxyethoxynaphthol

[0436] Sodium hydride (60%, 5.3 g, 134 mmol) was added in small portionsto a mixture of 6-bromo-2-naphthol (25.0 g, 112 mmol),2-bromoethylmethylether (17.1 g, 123 mmol) and dimethylformamide (150ml). The mixture was stirred at room temperature for 5 h. Aqueous sodiumhydroxide (200 ml, 1 M) was added, and the mixture was allowed to stirovernight. The crystals were filtered. Yield 28.2 g, 89%. Mp 54-55° C.

Example 2 Biological Activity

[0437] The affinity of compounds of the invention for nicotinic AChreceptors have been investigated in three test for in vitro inhibitionof ³H-epibatidin binding, ³H-α-bungarotoxin binding and ³H-cytisinebinding as described below.

In Vitro Inhibition of ³H-Cytisine Binding

[0438] The predominant subtype with high affinity for nicotine iscomprised of α₄ and β₂ subunits. nAChRs of the latter type canselectively be labelled by the nicotinic ACh modulator ³H-cytisine.

[0439] Tissue Preparation:

[0440] Preparations are performed at 0-4° C. Cerebral corticies frommale Wistar rats (150-250 g) are homogenised for 20 sec in 15 ml Tris,HCl (50 mM, pH 7.4) containing 120 mM NaCl, 5 mM KCl, 1 mM MgCl₂ and 2.5mM CaCl₂ using an Ultra-Turrax homogeniser. The homogenate iscentrifuged at 27,000×g for 10 min. The supernatant is discarded and thepellet is resuspended in fresh buffer and centrifuged a second time. Thefinal pellet is resuspended in fresh buffer (35 ml per g of originaltissue) and used for binding assays.

[0441] Assay:

[0442] Aliquots of 500 μl homogenate are added to 25 μl of test solutionand 25 μl of ³H-cytisine (1 nM, final concentration), mixed andincubated for 90 min at 2° C. Non-specific binding is determined using(−)-nicotine (100 μM, final concentration). After incubation the samplesare added 5 ml of ice-cold buffer and poured directly onto Whatman GF/Cglass fibre filters under suction and immediately washed with 2×5 mlice-cold buffer. The amount of radioactivity on the filters isdetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non-specific binding.

In Vitro Inhibition of ³H-α-Bungarotoxin Binding Rat Brain

[0443] α-Bungarotoxin is a peptide isolated from the venom of theElapidae snake Bungarus multicinctus (Mebs et al., Biochem. Biophys.Res. Commun., 44(3), 711 (1971)) and has high affinity for neuronal andneuromuscular nicotinic receptors, where it acts as a potent antagonist.³H-α-Bungarotoxin binds to a single site in rat brain with an uniquedistribution pattern in rat brain (Clarke et al., J. Neurosci. 5,1307-1315 (1985)).

[0444]³H-α-Bungarotoxin labels nAChR formed by the α₇ subunit isoformfound in brain and the α₁ isoform in the neuromuscular junction(Changeaux, Fidia Res. Found. Neurosci. Found. Lect. 4, 21-168 (1990).Functionally, the α₇ homo-oligomer expressed in oocytes has a calciumpermeability greater than neuromuscular receptors and, in some instancesgreater than NMDA channels (Seguela et al., J. Neurosci. 13, 596-604(1993).

[0445] Tissue preparation:

[0446] Preparations are performed at 0-4° C. Cerebral cortices from maleWistar rats (150-250 g) are homogenised for 10 sec in 15 ml 20 mM Hepesbuffer containing 118 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO₄ and 2.5 mM CaCl₂(pH 7.5) using an Ultra-Turrax homogeniser. The tissue suspension iscentrifuged at 27,000×g for 10 min. The supernatant is discarded and thepellet is washed twice by centrifugation at 27,000×g for 10 min in 20 mlfresh buffer, and the final pellet is resuspended in fresh buffercontaining 0.01% BSA (35 ml per g of original tissue) and used forbinding assays.

[0447] Assay:

[0448] Aliquots of 500 μl homogenate are added to 25 μl of test solutionand 25 μl of ³H-α-bungarotoxin (2 nM, final concentration), mixed andincubated for 2 h at 37° C. Non-specific binding is determined using(−)-nicotine (1 mM, final concentration). After incubation the samplesare added 5 ml of ice-cold Hepes buffer containing 0.05% PEI and poureddirectly onto Whatman GF/C glass fibre filters (presoaked in 0.1% PEIfor at least 6 h) under suction and immediately washed with 2×5 mlice-cold buffer. The amount of radioactivity on the filters isdetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non-specific binding.

In Vitro Inhibition of ³H-Epibatidin Binding

[0449] Epibatidin is an alkaloid that was first isolated from the skinof the Ecuadoran frog Epipedobates tricolor and was found to have veryhigh affinity for neuronal nicotinic receptors, where it acts as apotent agonist. ³H-epibatidin binds to two sites in rat brain, both ofwhich have pharmacological profiles consistent with neuronal nicotinicreceptors and a similar brain regional distribution (Hougling et al.,Mol. Pharmacol. 48, 280-287 (1995)).

[0450] The high affinity binding site for ³H-epibatidin is mostcertainly binding to the α₄β₂ subtype of nicotinic receptors. Theidentity of the low affinity site is still unknown; does it represent asecond nicotinic receptor or a second site in the same receptor. Theinability of α-bungarotoxin to compete for ³H-epibatidin binding sitesindicates that neither site measured represents the nicotinic receptorcomposed of α₇ subunits.

[0451] Tissue preparation:

[0452] Preparations are performed at 0-4° C. The forebrain (÷cerebellum)from a male Wistar rat (150-250 g) is homogenised for 10-20 sec in 20 mlTris, HCl (50 mM, pH 7.4) using an Ultra-Turrax homogeniser. The tissuesuspension is centrifuged at 27,000×g for 10 min. The supernatant isdiscarded and the pellet is washed three times by centrifugation at27,000×g for 10 min in 20 ml fresh buffer, and the final pellet isresuspended in fresh buffer (400 ml per g of original tissue) and usedfor binding assays.

[0453] Assay:

[0454] Aliquots of 2.0 ml homogenate are added to 0.100 ml of testsolution and 0.100 ml of ³H-epibatidin (0.3 nM, final concentration),mixed and incubated for 60 min at room temperature. Non-specific bindingis determined using (−)-nicotine (30 μM, final concentration). Afterincubation the samples are poured directly onto Whatman GF/C glass fibrefilters (presoaked in 0.1% PEI for at least 20 min) under suction andimmediately washed with 2×5 ml ice-cold buffer. The amount ofradioactivity on the filters is determined by conventional liquidscintillation counting. Specific binding is total binding minusnon-specific binding.

[0455] Results are given as IC₅₀ values; the concentration (μM) thatinhibit binding of the radioactive ligand by 50%.

1. A chemical compound having the general formula

in labelled or unlabelled form, or any of its enantiomers or any mixturethereof, or a pharmaceutically acceptable salt thereof; wherein - - -represents a single or a double bond; R represents hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, a mono- or polycyclicaryl group, or aralkyl; and R¹ represents a group of the formula

wherein R² represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, amino or a fluorescent group; or R¹ represents an mono-or polycyclic aryl group, which aryl group is substituted one or moretimes with substituents selected from the group consisting of alkyl,cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, methylenedioxy, hydroxy,alkoxy, alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen,OCF₃, CN, amino, carbamoyl, nitro, a mono- or polycyclic aryl group, amonocyclic 5- or 6-membered, saturated, partially saturated orunsaturated heterocyclic group, and a group of the formula—X—R′(—Y—R″)_(n); wherein X and Y independently of each anotherrepresent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independentlyof each another represent alkyl or cycloalkyl; or a fluorescent group;or R¹ represents a monocyclic 5- or 6- membered, saturated, partiallysaturated or unsaturated heterocyclic group, which heterocyclic groupmay be substituted one or more times with substituents selected from thegroup consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, methylenedioxy, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,aryloxy, alkylcarbonyloxy, halogen, CF₃, OCF₃, CN, sulfanyl, nitro, amono- or polycyclic aryl group, a monocyclic 5- or 6- membered,saturated, partially saturated or unsaturated heterocyclic group, and agroup of the formula —X—R′(—Y—R″)_(n); wherein X and Y independently ofeach another represent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″independently of each another represent alkyl or cycloalkyl; or afluorescent group; or R¹ represents a bi-cyclic heterocyclic groupcomposed of a monocyclic 5- or 6-membered heterocyclic group with oneheteroatom, fused to a benzene ring or fused to another monocyclic 5- or6- membered, saturated, partially saturated or unsaturated heterocyclicgroup, all of which is substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, methylenedioxy, hydroxy, alkoxy,alkoxy-alkyl, alkoxy-alkoxy, aryloxy, alkylcarbonyloxy, halogen, CF₃,OCF₃, CN, sulfanyl, amino, nitro, a mono- or polycyclic aryl group, amonocyclic 5- or 6- membered, saturated, partially saturated orunsaturated heterocyclic group, and a group of the formula—X—R′(—Y—R″)_(n); wherein X and Y independently of each anotherrepresent oxygen or sulphur, n is 0, 1 or 2, and R′ and R″ independentlyof each another represent alkyl or cycloalkyl; or a fluorescent group.2. A chemical compound of claim 1, wherein R¹ represents a 1-naphthylgroup, a 2-naphthyl group, a 3-naphthyl group or a 4-naphthyl group;which naphthyl groups may be substituted one or more times at the 5, 6,7 or 8-positions.
 3. The chemical compound of claim 2, wherein Rrepresents hydrogen or alkyl; and R¹ represents a 1-naphthyl group or a2-naphthyl group; which naphthyl groups may be substituted one or moretimes with substituents selected from the group consisting of halogen,amino, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, alkylcarbonyloxy,sulfanyl, alkylsulfanyl, alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl,alkylsulfanyl-alkylsulfanyl, pyrrolidinyl, piperidinyl, piperazinyl, andhomopiperazinyl.
 4. The chemical compound of claim 3, wherein R¹represents acetoxy-naphthyl, methoxy-naphthyl, hydroxy-naphthyl,bromo-naphthyl, methoxymethoxy-naphthyl, methoxyethoxy-naphthyl,ethylsulfanyl-naphthyl, methylsulfanyl-naphthyl, ethoxy-naphthyl,sulfanyl-naphthyl, methoxyethylsulfanyl-naphthyl, ethoxyethoxy-naphthyl,amino-naphthyl, dimethylamino-naphthyl, diethylamino-naphthyl,pyrrolidinyl-naphthyl, piperidinyl-naphthyl, piperazinyl-naphthyl, orhomopiperazinyl-naphthyl.
 5. A compound of claim 1 which is(±)-3-[1-(2-Iodophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct2-ene;(±)-3-[1-(2-Bromophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-(2-Chlorophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-(2-iodophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-(2-bromophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-(2-chlorophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(hydroxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;Exo-3-[6-(methoxymethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;(±)-3-[6-(acetyloxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(ethylsulfanyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(methylsulfanyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(ethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(sulfanyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(2-methoxyethylsulfanyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(2-ethoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-bromo-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-amino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-dimethylamino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-diethylamino-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(N-pyrrolidinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(N-piperidinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-8-methyl-3-[6-(N-piperazinyl)-2-naphthyl]-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-(N-homopiperazinyl)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;Exo-3-[6-(2-methoxyethoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;Exo-3-[6-methoxy)-2-naphthyl]-8-methyl-8-azabicyclo[3.2.1]octane;(±)-3-[6-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Bromo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Fluoro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Chloro-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or(±)-3-[7-Iodo-2-naphtyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or apharmaceutically acceptable addition salt thereof.
 6. The chemicalcompound of claim 1, wherein R¹ represents a monocyclic 5- or 6-memberedheterocyclic group, which heterocyclic group may be un-saturated,partially un-saturated or saturated, and may contain one or twoheteroatoms selected from the group consisting of N, S, O and Se.
 7. Thechemical compound of claim 6, wherein R¹ represents a 5-memberedheterocyclic group selected from the group consisting of dioxolanyl,furanyl, furazanyl, imidazolyl, isoimidazolyl, isopyrrolyl,isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyrrolidinyl,selenophene-yl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.
 8. Thechemical compound of claim 7, wherein R¹ represents a 5-memberedheterocyclic group selected from the group consisting of 2-furanyl,2-thienyl, 4-thiazolyl, 5-imidazolyl, 5-triazolyl, 2-pyrrolyl,2-selenophene-yl, 3-thiadiazolyl, 5-isoxazolyl, 5-oxazolyl, 5-pyrazolyl,5-isothiazolyl, 5-furazanyl; which heterocyclic groups may besubstituted one or more times with substituents selected from the groupconsisting halogen, amino, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy,sulfanyl, alkylsulfanyl, alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, andalkylsulfanyl-alkylsulfanyl.
 9. The chemical compound of claim 6,wherein R¹ represents a 6-membered heterocyclic group selected from thegroup consisting of dioxanyl, morpholinyl, oxazinyl, piperazinyl,piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyridinyl, andpyrimidinyl.
 10. The chemical compound of claim 9, wherein R¹ representsa 6-membered heterocyclic group selected from the group consisting of3-pyridyl, 4-pyridazyl, 4-pyrimidyl, and 3-pyrazinyl; which heterocyclicgroups may be substituted one or more times with substituents selectedfrom the group consisting halogen, amino, hydroxy, alkoxy, alkoxy-alkyl,alkoxy-alkoxy, sulfanyl, alkylsulfanyl, alkylsulfanyl-alkoxy,alkoxy-alkylsulfanyl, and alkylsulfanyl-alkylsulfanyl.
 11. The chemicalcompound of claim 1, wherein R¹ represents a bi-cyclic heterocyclicgroup selected from the group consisting of 5 or 6-benzimidazolyl, 5 or6-benzofuranyl, 5 or 6-benzothiazolyl, 5 or 6-benzothienyl, 5 or6-benzotrizolyl, 6 or 7-cinnolinyl, 5 or 6-indazolyl, 5 or6-indolizinyl, 5 or 6-indolyl, 5 or 6-isoindolyl, 6 or 7-isoquinolinyl,6-phthalazinyl, 6 or 7-quinolinyl, 6 or 7-quinolizinyl, and 6 or7-quinoxalinyl; which heterocyclic groups may be substituted one or moretimes with substituents selected from the group consisting halogen,amino, hydroxy, alkoxy, alkoxy-alkyl, alkoxy-alkoxy, sulfanyl,alkylsulfanyl, alkylsulfanyl-alkoxy, alkoxy-alkylsulfanyl, andalkylsulfanyl-alkylsulfanyl.
 12. A compound of claim 1 which is(±)-3-[2-(3-Bromofuranyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Bromofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Bromofuranyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Chlorofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Iodofuranyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Bromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Bromothienyl)]-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Bromothienyl)]-8-H-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Iodoothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3,4-Dibromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3,4-Dichlorothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(5-Bromothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(5-Chlorothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(5-Iodothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Bromo-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Chloro-1-methyl-imidazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Iodo-1-methyl-imidzolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Bromo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Chloro-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Iodo-1-methyl-1,2,3-triazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Bromo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Chloro-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Iodo-1-methyl-pyrrolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Bromoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Chloroselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-(3-Iodoselenophenyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(4-Bromo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(4-Chloro-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(4-Iodo-1-2-5-thiadiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Bromo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Chloro-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Iodo-isoxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Bromo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Chloro-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Iodo-oxazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Bromo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Chloro-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Iodo-1-methylpyrazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Bromo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Chloro-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Iodo-isothiazolyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Bromo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Chloro-furazanyl)]-8-methyl-8azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-(4-Iodo-furazanyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(2-Bromo-pyridyl)]-8methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(2-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(4-Bromo-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(4-Chloro-pyridyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(3-Bromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(3-Chloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(3,6-Dibromo-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(3,6-Dichloro-pyridazyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(5-Bromo-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[4-(5-Chloro-pyrimidyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(2,6-dichloropyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[3-(2-Chloro-pyrazinyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Quinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Isoquinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Quinolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-H-5-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-H-6-Benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-H-5-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-H-6-Benzotrizolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-Amino-1-H-5-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-Amino-1-H-6-benzimidazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-phthalazinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Benzofuranyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Benzothienyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[5-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Benzothiazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-Methyl-5-indolyl]-8-methyl-3-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-Methyl-6-indolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Indolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-Methyl-5-isoindolyl]-8methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[2-Methyl-6-isoindolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-Methyl-5-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[1-Methyl-6-indazolyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Quinolizinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[7-Cinnolinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;(±)-3-[6-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or(±)-3-[7-Quinoxalinyl]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or apharmaceutically acceptable addition salt thereof.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of thechemical compound of any of claims 1-12, or a pharmaceuticallyacceptable addition salt thereof, together with at least onepharmaceutically acceptable carrier or diluent.
 14. An assay kitcomprising the pharmaceutical composition according to claim 13 in aunit dosage form in a suitable container.
 15. An assay kit according toclaim 14 further comprising a stabilising composition.
 16. The use ofthe chemical compound according to any of claims 1-12 for themanufacture of a medicament for the treatment or alleviation of adisease or disorder of a living animal body, including a human, whichdisease or disorder is responsive to the action of a nicotinic AcetylCholine Receptor (nAChR) modulator.
 17. The use according to claim 16,wherein the disease or disorder to be treated is a disease or disorderof the central nervous system, a disease or disorder caused by orrelated to smooth muscle contraction, an endocrine disorder, a diseaseor disorder caused by or related to neuro-degeneration, a disease ordisorder caused by or related to inflammation, pain, a withdrawalsymptom caused by the termination of abuse of chemical substances. 18.The use of a compound according to claim 17, wherein the disease ordisorder of the central nervous system is anxiety, cognitive disorders,learning deficit, memory deficits and dysfunction, Alzheimer's disease,attention deficit, attention deficit hyperactivity disorder, Parkinson'sdisease, Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles dela Tourettes syndrome, depression, mania, manic depression,schizophrenia, obsessive compulsive disorders (OCD), panic disorders,eating disorders such as anorexia nervosa, bulimia and obesity,narcolepsy, nociception, AIDS-dementia, senile dementia, perifericneuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia,epilepsy, bulimia, post-traumatic syndrome, social phobia, chronicfatigue syndrome, sleeping disorders, pseudodementia, Ganser's syndrome,pre-menstrual syndrome, late luteal phase syndrome, chronic fatiguesyndrome, mutism, trichotillomania, and jetlag.
 19. The use according toclaim 17, wherein the disease or disorder caused by or related to smoothmuscle contraction is convulsive disorders, angina pectoris, prematurelabor, convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia,hyperkinesia, premature ejaculation, and erectile difficulty.
 20. Theuse according to claim 17, wherein the endocrine disorder isthyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.
 21. Theuse according to claim 17, wherein the neuro-degenerative disease istransient anoxia and induced neurodegeneration.
 22. The use according toclaim 17, wherein the disease or disorder caused by or related toinflammation is an inflammatory skin disorder such as acne and rosacea,Chron's disease, inflammatory bowel disease, ulcerative collitis, anddiarrhoea.
 23. The use according to claim 17, wherein pain is a mild, amoderate or a severe pain of acute, chronic or recurrent character, apain caused by migraine, a postoperative pain, or a phantom limb pain.24. The use according to claim 17, wherein the addictive substance is anicotine containing product such as tobacco, an opioids such as heroin,cocaine or morphine, a benzodiazepine or a benzodiazepin-like drug, oralcohol.
 25. The use of the chemical compound according to any of claims1-12, or any of its enantiomers or any mixture thereof, in labelled orunlabelled form, for the manufacture of a diagnostic agent for thediagnosis of a disorder or disease of a living animal body, including ahuman, which disease or disorder is responsive to the action of anicotinic Acetyl Choline Receptor (nAChR) modulator.
 26. A method forthe preparation of the compounds according to claims 1-12, which methodcomprises A) the step of reacting a compound having the formula

wherein R is as defined in claim 1, with a compound of the formulaR¹—Li, wherein R¹ is as defined in claim 1, followed by dehydration ofthe compound obtained; or B) the step of reacting a compound having theformula

wherein R is as defined in claim 1, with a compound of formula R¹—X,wherein R¹ is as defined in claim 1, and X represents halogen, boronicacid, or trialkylstannyl; or C) the step of reducing a compound havingthe formula

wherein R¹ is as defined in claim
 1. 27. A method of the treatment oralleviation of a disease or disorder of a living animal body, includinga human, which disease or disorder is responsive to the action of anicotinic Acetyl Choline Receptor (nAChR) modulator, which methodcomprises the step of administering to such a living animal body,including a human, in need thereof a therapeutically effective amount ofthe chemical compound according to any of claims 1-12.
 28. The methodaccording to claim 27, wherein the disease or disorder to be treated isa disease or disorder of the central nervous system, a disease ordisorder caused by or related to smooth muscle contraction, an endocrinedisorder, a disease or disorder caused by or related toneuro-degeneration, a disease or disorder caused by or related toinflammation, pain, a withdrawal symptom caused by the termination ofabuse of chemical substances.
 29. The method of claim 28, wherein thedisease or disorder of the central nervous system is anxiety, cognitivedisorders, learning deficit, memory deficits and dysfunction,Alzheimer's disease, attention deficit, attention deficit hyperactivitydisorder, Parkinson's disease, Huntington's disease, Amyotrophic LateralSclerosis, Gilles de la Tourettes syndrome, depression, mania, manicdepression, schizophrenia, obsessive compulsive disorders (OCD), panicdisorders, eating disorders such as anorexia nervosa, bulimia andobesity, narcolepsy, nociception, AIDS-dementia, senile dementia,periferic neuropathy, autism, dyslexia, tardive dyskinesia,hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia,chronic fatigue syndrome, sleeping disorders, pseudodementia, Ganser'ssyndrome, pre-menstrual syndrome, late luteal phase syndrome, chronicfatigue syndrome, mutism, trichotillomania, and jetlag
 30. The method ofclaim 28, wherein the disease or disorder caused by or related to smoothmuscle contraction is convulsive disorders, angina pectoris, prematurelabor, convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia,hyperkinesia, premature ejaculation, and erectile difficulty.
 31. Themethod of claim 28, wherein the endocrine disorder is thyrotoxicosis,pheochromocytoma, hypertension and arrhythmias.
 32. The method of claim28, wherein the neuro-degenerative disease is transient anoxia andinduced neurodegeneration.
 33. The method of claim 28, wherein thedisease or disorder caused by or related to inflammation is aninflammatory skin disorder such as acne and rosacea, Chron's disease,inflammatory bowel disease, ulcerative collitis, and diarrhoea.
 34. Themethod of claim 28, wherein pain is a mild, a moderate or a severe painof acute, chronic or recurrent character, a pain caused by migraine, apostoperative pain, or a phantom limb pain.
 35. The method of claim 28,wherein the addictive substance is a nicotine containing product such astobacco, an opioids such as heroin, cocaine or morphine, abenzodiazepine or a benzodiazepin-like drug, or alcohol.
 36. A methodfor the non-invasive determination of the distribution of a tracercompound inside a whole, intact living animal or human body using aphysical detection method, wherein the tracer compound is a compoundaccording to any of the claims 1-12, or any of its enantiomers or anymixture thereof, or a pharmaceutically acceptable salt thereof, inlabelled or unlabelled form.
 37. The method of claim 36, wherein thephysical detection method is selected from PET, SPECT; MRS, MRI, CAT, orcombinations thereof.